N-aminobutyl-n-phenylarylamide compounds and their application in therapy

ABSTRACT

A compound of formula (I) ##STR1## in which: X denotes hydrogen, a halogen, a trifluoromethyl group, a C 1  -C 4  alkyl group or a C 1  -C 4  alkoxy group; 
     R 1  denotes a linear or branched C 2  -C 8  alkyl group, a C 3  -C 5  cycloalkyl group or a cycloalkylmethyl group in which the cycloalkyl moiety has from 3 to 5 carbon atoms; 
     R 2  denotes hydrogen or a C 1  -C 4  alkyl group; 
     R 3  denotes hydrogen, a C 1  -C 4  alkyl group, an optionally substituted phenylalkyl group or a pyridylalkyl group; 
     or R 2  and R 3  denote, together with the nitrogen to which they are attached, a pyrrolidinyl, piperidyl, morpholinyl, perhydrothiazinyl, piperazinyl or 4-methylpiperazinyl ring; and 
     Ar denotes a phenyl group, optionally having from one to three substituents, each of which is, independently, a halogen or a C 1  -C 4  alkyl, C 1  -C 4  alkoxy, trifluoromethyl, nitro or cyano group, or Ar denotes a naphthyl, pyridyl, quinolinyl or isoquinolinyl group; 
     or a pharmacologically acceptable acid addition salt thereof.

This application is a continuation of application Ser. No. 218,873,filed July 14, 1988, abandoned.

The present invention relates to N-aminobutyl-N-phenylarylamidederivatives, their preparation and their application in therapy.

The present invention provides a compound of formula (I) ##STR2## inwhich: X denotes hydrogen, a halogen, a trifluoromethyl group, a C₁ -C₄alkyl group or a C₁ -C₄ alkoxy group;

R₁ denotes a linear or branched C₂ -C₈ alkyl group, a C₃ -C₅ cycloalkylgroup or a cycloalkylmethyl group in which the cycloalkyl moiety hasfrom 3 to 5 carbon atoms;

R₂ denotes hydrogen or a C₁ -C₄ alkyl group;

R₃ denotes hydrogen, a C₁ -C₄ alkyl group, an optionally substitutedphenylalkyl group or a pyridylalkyl group;

or R₂ and R₃ denote, together with the nitrogen to which they areattached, a pyrrolidinyl, piperidyl, morpholinyl, perhydrothiazinyl,piperazinyl or 4-methylpiperazinyl ring; and

Ar denotes a phenyl group, optionally having from one to threesubstituents, each of which is, independently, a halogen or a C₁ -C₄alkyl, C₁ -C₄ alkoxy, methylenedoxy trifluoromethyl, nitro or cyanogroup, or Ar denotenotes a naphthyl, pyridyl, quinolinyl orisoquinolinyl group.

Preferred compounds are those in which R₁ denotes an isobutyl group andAr denotes a substituted phenyl group, and those in which X denoteshydrogen and R₂ denotes a methyl group. Especially preferred compoundsare those in which R₃ denotes a methyl group and Ar denotes a.2,3-dimethylphenyl, 3-trifluoromethylphenyl, 3-nitrophenyl or2-methoxy-3-nitrophenyl group; those in which R₃ denotes a2-(3-methoxyphenyl)-ethyl, 2-(3,4-dimethoxyphenyl)ethyl or2-(3-pyridyl)ethyl group and Ar denotes a 3-trifluoromethylphenyl group;and those in which R₁ denotes a 2-(3,4-dimethoxyphenyl)ethyl group andAr denotes a 2-methyl-3-nitrophenyl group.

The present invention provides a process for preparing a compound offormula (I), which comprises acylating a diamine of formula (II)##STR3## in which X, R₁, R₂ and R₃ are as defined above, with an acidchloride of formula (III)

    ArCOCl                                                     (III)

in which Ar is as defined above.

The acylation is preferably carried out in the cold, in a solvent and inthe presence of a base such as potassium carbonate.

The diamine of formula (II) may be obtained, for example, by a processas illustrated in each of the Schemes 1a and 1b below.

According to Scheme 1a, a primary benzenamine of formula (IV), in whichX and R₁ are as defined above, is first acylated with 4-chlorobutanoylchloride of formula (V), generally in the cold and in the presence of abase. The amide of formula (VI) thereby obtained is then reacted with anamine of the formula (VII), in which R₂ and R₃ are as defined above,generally in a solvent such as acetonitrile, dimethylformamide, ethanolor tetrahydrofuran, preferably in the heated state, in the presence ofpotassium iodide, a phase transfer agent such as tetrabutylammoniumiodide and a base such as potassium carbonate.

Finally, the amide of formula (VIII) thereby obtained is reduced, using,for example, lithium aluminium hydride or diborane or an alkali metalborohydride, preferably in a solvent in the heated state.

According to Scheme 1b, an acetamide of formula (IX), in which X and R₁are as defined above, which may itself be prepared in a known mannerfrom a benzenamine of formula (IV) is reacted with1-bromo-4-chlorobutane of formula (X), generally in the cold, in anaprotic polar solvent such as dimethylformamide, dimethyl sulphoxide oracetone, in the presence of a base such as sodium hydride, potassiumhydroxide or potassium carbonate. The compound of the formula (XI)thereby obtained is then reacted with an amine of formula (VII), inwhich R₁ and R₃ are as defined above, in a manner similar to thatdescribed above in relation to the reaction between the amide of formula(VI) and the amine of formula (VII).

A compound of formula (XII) is thereby obtained, which can be convertedto the diamine of formula (II), for example, by adding water and a basesuch as potassium tert-butylate or potassium hydroxide, in the heatedstate and in a solvent such as tetrahydrofuran or dioxane.

The present invention provides another process for preparing a compoundof formula (I) which comprises reacting a compound of formula (XIV)##STR4## in which X, R₁ and Ar are as defined above with an amine offormula (VII)

    HNR.sub.2 R.sub.3                                          (VII)

in which R₂ and R₃ are as defined above.

The conditions of reaction are preferably similar to those describedabove in relation to the reaction between the amide of formula (VI) andthe amine of formula (VII).

The compound of formula (XIV) may be prepared, for example, by reactinga compound of formula (XIII) ##STR5## wherein X, R₁ and Ar are asdefined above with 1-bromo 4-chlorobutane.

The reaction conditions are generally similar to those described abovein relation to the reaction between the acetamide of formula (IX) and1-bromo-4-chlorobutane.

The compound of formula (XIII) may, for example, be prepared byacylating a compound of formula (IV) ##STR6## in which X and R₁ are asdefined above with an acid chloride of formula (III)

    ArCOCl                                                     (III)

in which Ar is as defined above.

This reaction is generally carried out at a temperature of from -10° to+30° C. in a solvent such as dichloromethane, ether or tetrahydrofuran,and in the presence of a base such as potassium carbonate, triethylamineor 4-(dimethylamino)pyridine.

The benzenamine of formula (IV) may be obtained according to variousknown methods.

It is possible, for example, to alkylate an N-(2-hydroxyphenyl)acetamidebearing a substituent X as defined above to obtain the correspondingN-(2-alkoxyphenyl)acetamide, and then to decompose the latter compoundto the benzenamine of formula (IV) by hydrolysis.

It is also possible to react a 2-halonitrobenzene bearing a substituentX as defined above with an alcohol of formula R OH to obtain thecorresponding 2-alkoxynitrobenzene, and then to reduce the lattercompound to the benzenamine of formula (IV).

Finally, it is possible to alkylate a 2-nitrophenol bearing asubstituent X, as defined above to obtain the corresponding2-alkoxynitrobenzene and to reduce the latter compound to thebenzenamine of formula (IV). ##STR7##

The Examples which follow illustrate in detail the preparation of a fewcompounds according to the invention. The microanalyses and IR and NMRSpectra of the products obtained confirm their structures.

The numbers appearing in brackets in the titles of the Examplescorrespond to those in the table given later.

EXAMPLE 1 (Compound No. 23)N-[4-(Dimethylamino)butyl]-N-[2-(2-methylpropoxy)phenyl]-2,5-dichlorobenzamidefumarate (a) 4-Chloro-N-[2-(2-methylpropoxy)phenyl]butanamide

A solution of 44 ml of 4-chlorobutyryl chloride in 350 ml of ether isadded dropwise to a suspension of 60 g of 2-(2-methylpropoxy)benzenamineand 199 g of potassium carbonate in 500 ml of ether, cooled in anicebath, and the mixture is stirred overnight at room temperature. Themixture is filtered and the filtrate washed successively with 200 ml of1 N sodium hydroxide, three times 100 ml o& water and 100 ml ofsaturated sodium chloride solution. The ethereal solution is dried overmagnesium sulphate and the solvent evaporated off. 85.8 g of syrupyproduct are collected, and used without further treatment in thefollowing stage.

(b) 4-(Dimethylamino)-N-[2-(2-methylpropoxy)phenyl]butanamide

The above product is dissolved in 620 ml of acetonitrile, and 126 g ofdimethylamine hydrochloride, 51.5 g of potassium iodide, 107 g ofpotassium carbonate and 5.7 g of tetra-n-butylammonium iodide are added.The mixture is heated to reflux for 7 h and filtered, washing the solidwith acetonitrile, and the filtrate is evaporated. The residue is takenup with 1,000 ml of ether and 500 ml of 1 N sodium hydroxide. Theorganic phase is separated off, washed with saturated sodium chloridesolution, dried over magnesium sulphate and evaporated under vacuum. 45g of crude product are obtained.

By extracting the aqueous phases three times with 200 ml ofdichloromethane, a further 19 g of product, which are added to the 45 galready isolated, are obtained after drying and evaporation. Thecombined product is purified by formation of the correspondinghydrochloride and recrystallization. After liberation of the base bytreatment with a base, 52 g of syrupy product are collected, and this isused without further treatment in the following stage.

(c) N,N-Dimethyl-N'-[2-(2-methylpropoxy)phenyl]-1,4-butanediamine

52 g of the above product are dissolved in 300 ml of tetrahydrofuran,and the solution obtained is added dropwise to a suspension of 14 g oflithium aluminium hydride in 600 ml of tetrahydrofuran, cooled in anicebath.

The mixture is then heated to reflux for 3 h, allowed to cool andtreated with a solution of 19 g of sodium hydroxide in 25 ml of water.

The mixture is diluted with 500 ml of ethyl acetate and filtered overmagnesium sulphate. The filtrate is evaporated and the residue distilledunder vacuum, which gives 31.3 g of product.

Boiling point: 118°-124° C. at 20 Pa (0.15 mmHg).

(d)N-[4-(Dimethylamino)butyl]-N-[2-(2-methylpropoxy)phenyl]-2,5-dichlorobenzamide

A solution of 2.3 g of 2,5-dichlorobenzoyl chloride in 30 ml of ether isadded dropwise to a mixture of 2.4 g of the above compound, 4 g ofpotassium carbonate and 30 ml of ether.

The mixture is stirred overnight and 100 ml of water and 40 ml of etherare then added. The organic phase is separated off, washed three timeswith 50 ml of water and then 50 ml of saturated sodium chloridesolution, dried over magnesium sulphate and evaporated under vacuum.After purification by chromatography on a silica column, 3.2 g of syrupyproduct are obtained.

3 g of this are dissolved in methanol, 0.8 g of fumaric acid is added,the solvent is driven off under vacuum and the residue is recrystallizedin ethyl acetate. 2.9 g of fumarate are obtained in the form of a whitepowder. Melting point: 130° C.

EXAMPLE 2 (Compound No. 2)N-[4-(Dimethylamino)butyl]-N-[2-(2-methylpropoxy)phenyl]-3-(trifluoromethyl)benzamidehydrochloride (a)N-(4-Chlorobutyl)-N-[2-(2-methylpropoxy)phenyl]acetamide

To a suspension of 10.3 g of lithium hydride (at a concentration of 50%in oil) in 100 ml of dimethylformamide, cooled in an ice-bath, there areadded dropwise 35.6 g of N-[2-(methylpropoxy)phenyl]acetamide dissolvedin 70 ml of dimethylformamide, and then 21.5 ml of1-bromo-4-chlorobutane.

The mixture is stirred for 5 h at room temperature; 400 ml of water and400 ml of ether are added, and the organic phase is separated off,washed three times with 50 ml of water and then with 25 ml of saturatedsodium chloride solution, dried over magnesium sulphate and evaporatedunder vacuum. 54.5 g of syrupy product are obtained, and this is usedwithout further treatment in the following stage.

(b) N-[4-(Dimethylamino)butyl]-N-[2-(2-methylpropoxy)phenyl]acetamide

The above product is dissolved in 120 ml of dimethylformamide, and 117 gof potassium carbonate, 20 g of potassium iodide, 3 g oftetra-n-butylammonium iodide and 69 g of dimethylamine hydrochloride areadded.

The mixture is stirred for 13 h at 70° C. and filtered, washing thesolid three times with 200 ml of ether; the filtrate is treated with 400ml of 0.1 N sodium hydroxide, and the organic phase is separated off,washed three times with 100 ml of water and then with 50 ml of saturatedsodium chloride solution, dried over magnesium sulphate and evaporatedunder vacuum. 42.1 g of syrupy product are obtained, and this is usedwithout further treatment in the following stage.

(c) N,N-Dimethyl-N'-[2-(2-methylpropoxy)phenyl]-1,4-butanediamine

The above product is dissolved in 280 ml of tetrahydrofuran, 4.9 ml ofwater and 92.4 g of potassium tertbutylate are added and the mixture isheated to reflux for 12 h. 200 ml of ice-cold water and 600 ml of etherare added, and the organic phase is separated off, washed four timeswith 100 ml of water and then with 50 ml of saturated sodium chloridesolution, dried over magnesium sulphate and evaporated under vacuum.After distillation of the residue under vacuum, 27.1 g of product areobtained.

Boiling point: 106°-110° C. at 13 Pa (0.1 mmHg).

(d)N-[4-(Dimethylamino)butyl]-N-[2-(2-methylpropoxy)phenyl]-3-(trifluoromethyl)benzamide

A suspension of 5.0 g of the above product and 10.1 g of potassiumcarbonate in 60 ml of dichloromethane is prepared and is cooled in anice-bath, and a solution of 3.4 ml of 3-(trifluoromethyl)benzoylchloride in 60 ml of dichloromethane is added.

The mixture is stirred overnight at room temperature, the solvent isevaporated off, the residue is taken up with 200 ml of ether and 100 mlof water, and the organic phase is separated off, washed three timeswith 100 ml of water and then with 100 ml of saturated sodium chloridesolution, dried over magnesium sulphate and evaporated. The residue ispurified by chromatography on a silica column and 6.4 g of syrupyproduct are obtained.

6.3 g of this are dissolved in 145 ml of a 0.1 N solution ofhydrochloric acid in isopropyl alcohol, the solution is evaporated undervacuum and the residue is recrystallized in an ethanol/diisopropyl ethermixture. 5.2 g of hydrochloride are obtained in the form of a whitepowder. Melting point: 146°-148° C.

EXAMPLE 3 (Compound No. 37)N-[4-{[2-(3,4-Dimethoxyphenyl)ethyl]methylamino}butyl]-N-[2-(2-methylpropoxy)phenyl]-3-(trifluoromethyl)benzamideoxalate (a) N-[2-(2-Methylpropoxy)phenyl]-3-(trifluoromethyl)benzamide

A solution of 12.5 g of 3.(trifluoromethyl)benzoyl chloride in 60 ml ofdichloromethane is added dropwise to a suspension of 9.9 g of2-(2-methylpropoxy)benzenamine and 33 g of potassium carbonate in 90 mlof dichloromethane, cooled in an ice-bath.

The mixture is stirred overnight at room temperature and the solvent isthen evaporated off. The residue is taken up with a mixture of 200 ml ofwater and 300 ml of ether, and the organic phase is separated off washedsuccessively with twice 50 ml of water, twice 50 ml of 1 N aqueoushydrochloric acid, three times 50 ml of water and 25 ml of saturatedsodium chloride solution. It is dried over magnesium sulphate andevaporated under vacuum. 19.7 g of syrupy product are obtained, and thisis used without further treatment in the following stage.

(b)N-(4-Chlorobutyl)-N-[2-(2-methylpropoxy)phenyl]-3-(trifluoromethyl)benzamide

To a suspension of 4 g of lithium hydride (at a concentration of 50% inoil) in a 80 ml of dimethylformamide, cooled in an ice-bath, there areadded dropwise the 19.7 g of the above product dissolved in 30 ml ofdimethylformamide, and then 7.95 ml of 1-bromo-4-chlorobutane.

The mixture is stirred overnight at room temperature, 250 ml of waterand 250 ml of ether are then added, the organic phase is separated off,the aqueous phase is extracted a second time with 250 ml of ether, theorganic phases are combined to a single phase, and the latter is washedwith 100 ml of water, then twice with 100 ml of 0.5 N aqueoushydrochloric acid, then three times with 50 ml of water and finally with50 ml of saturated sodium chloride solution. It is dried over magnesiumsulphate and evaporated under vacuum. 24.2 g of syrupy product areobtained, and this is used without further treatment in the followingstage.

(c)N-[4-{[2-(3,4-Dimethoxyphenyl]methylamino}butyl]-N-[2-(2-methylpropoxy)phenyl]-3-(trifluoromethyl)benzamide

A mixture of 2.14 g of the above product, 1.46 g ofN-[2-(3,4-dimethoxyphenyl)ethyl]methylamine, 2.07 g of potassiumcarbonate, 0.8 g of potassium iodide and 0.09 g of tetra-n-butylammoniumiodide in 25 ml of dimethylformamide is stirred at 80° C. for 12 h.

250 ml of ether and 50 ml of 0.5 N sodium hydroxide are then added, andthe organic phase is separated off, washed three times with 50 ml ofwater and then with 25 ml of saturated sodium chloride solution, driedover magnesium sulphate and evaporated. The residue is purified bychromatography on a silica column and 2.4 g of syrupy product areobtained.

2.15 g of this are dissolved in 150 ml of ether and a solution of 0.33 gof oxalic acid in 50 ml of ether is added dropwise.

The mixture is left standing overnight at room temperature, and theprecipitate is separated off by filtration, washed with ether andrecrystallized in a mixture of 40 ml of isopropyl alcohol and 260 ml ofdiisopropyl ether.

1.6 of oxalate are obtained in the form of a white powder.

Melting point: 80°-82° C.

The table below illustrates the structures and physical properties of afew compounds according to the invention.

                                      TABLE    __________________________________________________________________________    Compound          R.sub.1  X    Ar          R.sub.2                                       R.sub.3          Salt                                                            M.p.    __________________________________________________________________________                                                            (°C.)     1    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.5                                    CH.sub.3                                       CH.sub.3         08  110-113     2    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                       CH.sub.3         10  146-148     3    CH.sub.2 CH(CH.sub.3).sub.2                   4-F  C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                       CH.sub.3         10  119-120     4    CH.sub.2 CH(CH.sub.3).sub.2                   5-Cl C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                       CH.sub.3         46  124-130     5    CH.sub.2 C(CH.sub.3).sub.3                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                       CH.sub.3         46  116-120     6    CH.sub.2 -cC.sub.3 H.sub.5                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                       CH.sub.3         10  118-120     7    CH.sub.2 -cC.sub.5 H.sub.9                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                       CH.sub.3         10  142-144     8    CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                       CH.sub. 3        10  134-136     9    cC.sub.5 H.sub.9          H        C.sub.6 H.sub.4 -3-CF.sub.3                        CH.sub.3    CH.sub.3                                       10               110-112    10    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -2-F                                    CH.sub.3                                       CH.sub.3         46  111-114    11    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -2-Cl                                    CH.sub.3                                       CH.sub.3         08  144-146    12    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -2-OCH.sub.3                                    CH.sub.3                                       CH.sub.3         08  150-152    13    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-NO.sub.2                                    CH.sub.3                                       CH.sub.3         46  146-148    14    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -2-NO.sub.2                                    CH.sub.3                                       CH.sub.3         46  112-114    15    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-F                                    CH.sub.3                                       CH.sub.3         10  122    16    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-Cl                                    CH.sub.3                                       CH.sub.3         10  135-136    17    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -2-CF.sub.3                                    CH.sub.3                                       CH.sub.3         46  133-134    18    CH.sub.2 CH(CH.sub.3 ).sub.2                   H    C.sub.6 H.sub.4 -3-CN                                    CH.sub.3                                       CH.sub.3         10  144-146    19    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2,3-(CH.sub.3).sub.2                                    CH.sub.3                                       CH.sub.3         46  138-140    20    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2-CH.sub.3 -3-NO.sub.2                                    CH.sub.3                                       CH.sub.3         46  148-150    21    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2-Cl-3-NO.sub.2                                    CH.sub.3                                       CH.sub.3         08  114-116    22    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2,3-Cl.sub.2                                    CH.sub.3                                       CH.sub.3         08  154-156    23    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2,5-Cl.sub.2                                    CH.sub.3                                       CH.sub.3         08  130    24    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2-Cl-6-F                                    CH.sub.3                                       CH.sub.3         08  152-154    25    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2-Cl-4-NO.sub.2                                    CH.sub.3                                       CH.sub.3         10  190-192    26    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2-Cl-5-NO.sub.2                                    CH.sub.3                                       CH.sub.3         10  166-168    27    CH.sub.2 CH(CH.sub.3).sub. 2                   H    C.sub.6 H.sub.3 -2,4-Cl.sub.2                                    CH.sub.3                                       CH.sub.3         10  180-182    28    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2-NO.sub.2 -5-Cl                                    CH.sub.3                                       CH.sub.3         10  140-142    29    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2-OCH.sub.3 -5-NO.sub.2                                    CH.sub.3                                       CH.sub.3         10  126-130    30    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2-Cl-5-Br                                    CH.sub.3                                       CH.sub.3         10  186-188    31    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -3,5-Cl.sub.2                                    CH.sub.3                                       CH.sub.3         46  156-158    32    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -3-NO.sub.2 -4-Cl                                    CH.sub.3                                       CH.sub.3         46  114-116    33    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -3,4-Cl.sub.2                                    CH.sub.3                                       CH.sub.3         46  139-141    34    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.5                                    (CH.sub.2).sub.4    46  110-112    35    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -4-OCH.sub.3                                    (CH.sub.2).sub.4    46  149    36    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                     ##STR8##           46  134-136    37    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR9##        46  80-82    38    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR10##       2.10                                                            146-149    39    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                       CH.sub.2 C.sub.6 H.sub.5                                                        46  160-162    40    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                     ##STR11##          15  142-144    41     CH.sub.2 CH(CH.sub.3).sub.2                   H    1-naphthyl  CH.sub.3                                       CH.sub.3         46  178-180    42    CH.sub.2 CH(CH.sub.3).sub.2                   H    1-isoquinolinyl                                    CH.sub.3                                       CH.sub.3         46  120-122    43    CH.sub.2 CH(CH.sub.3).sub.2                   H    4-quinolinyl                                    CH.sub.3                                       CH.sub.3         46  146-148    44    CH.sub.2 CH(CH.sub.3).sub.2                   4-CH.sub.3                        1-naphthyl  CH.sub.3                                       CH.sub.3         1/208                                                            150-151    45    CH.sub.2 CH(CH.sub.3).sub.2                   4-F  1-naphthyl  CH.sub.3                                       CH.sub.3         1/208                                                            174-176    46    CH.sub.2 CH(CH.sub.3).sub.2                   5-Cl 1-naphthyl  CH.sub.3                                       CH.sub.3         10  104-108    47    CH.sub.2 CH(CH.sub.3).sub.2                   4-OCH.sub.3                        1-naphthyl  CH.sub.3                                       CH.sub.3         1/208                                                            152-154    48    CH.sub.2 CH(CH.sub.3).sub.2                   5-CH.sub.3                        1-naphthyl  CH.sub.3                                       CH.sub.3         46  114-118    49    CH.sub.2 CH(CH.sub.3).sub.2                   5-CF.sub.3                        1-naphthyl  CH.sub.3                                       CH.sub.3         46  156-158    50    CH.sub.2 CH(CH.sub.3).sub.2                   H    1-naphthyl  C.sub.3 H.sub.7                                       C.sub.3 H.sub.7  10  120    51    CH.sub.2 CH(CH.sub.3).sub.2                   H    1-naphthyl  (CH.sub.2).sub.5    10  198-200     51a  CH.sub.2 CH(CH.sub.3).sub.2                   H    2-naphthyl  CH.sub.3                                       CH.sub.3         08  152-154     51b  CH.sub.2 CH(CH.sub.3).sub.2                   H    3-pyridyl   CH.sub.3                                       CH.sub.3         10  104-106    52    CH.sub.2 CH(CH.sub.3).sub.2                   H    1-naphthyl                                     ##STR12##          10  188-190    53    CH.sub.2 CH(CH.sub.3).sub.2                   H    1-naphthyl                                     ##STR13##          10  214-216    54    CH.sub.2 CH(CH.sub.3).sub.2                   H    1-naphthyl                                     ##STR14##          10  110-120    55    CH.sub.2 CH(CH.sub.3).sub.2                   H    1-naphthyl  CH.sub.3                                        ##STR15##       46  87-93    56    CH.sub.2 CH(CH.sub. 3).sub.2                   H    C.sub.6 H.sub.3 -2-Cl-5-NO.sub.2                                    CH.sub.3                                        ##STR16##       46  143-145    57    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR17##       46  136-138    58    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR18##       10  151-153    59    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -4-CF.sub.3                                    CH.sub.3                                        ##STR19##       46  128-130    60    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2-OCH.sub.3 -5-NO.sub.2                                    CH.sub.3                                        ##STR20##       10  158-160    61    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2,5-Cl.sub.2                                    CH.sub.3                                        ##STR21##       10  78-80    62    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2-CH.sub.3 -3-NO.sub.2                                    CH.sub.3                                        ##STR22##       10  104-106    63    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -3,4-(OCH.sub.3).sub.2                                    CH.sub.3                                        ##STR23##       46  81-83    64    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -3,4-OCH.sub.2 O                                    CH.sub.3                                        ##STR24##       46  133-134    65    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.2 -3,4,5-(OCH.sub.3).sub.3                                    CH.sub.3                                        ##STR25##       46  90-94    66    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-NO.sub.2                                    CH.sub.3                                        ##STR26##       10  120-122    67    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2,3-(CH.sub.3).sub.2                                    CH.sub.3                                        ##STR27##       46  80-84    68    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.3 -2,3-Cl.sub.2                                    CH.sub.3                                        ##STR28##       46  98-100    69    CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR29##       46  115-117    70    C(CH.sub.2).sub.3                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR30##       46  128-130    71    cC.sub.5 H.sub.9          H        C.sub.6 H.sub.4 -3-CF.sub.3                        CH.sub.3                                     ##STR31##                                       46               132-134    72    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    H                                        ##STR32##       08  132-134    73    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR33##       46  66-70    74    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR34##       46  122-124    75    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR35##       2.46 2.10                                                            112-116 140-150    76    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR36##       10  138-140    77    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR37##       46  122-124    78    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR38##       46  104-108    79    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR39##       10  120-124    80    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR40##       10  114-118    81    CH.sub.2 CH(CH.sub.3).sub.2                   H    C.sub.6 H.sub.4 -3-CF.sub.3                                    CH.sub.3                                        ##STR41##       46  88-90    __________________________________________________________________________     Legend to the table     "R1" column: cC.sub.3 H.sub.5 and cC.sub.5 H.sub.9 denote cyclopropyl and     cyclopentyl groups, respectively.     "Ar" column: C.sub.6 H.sub.5, C.sub.6 H.sub.4, C.sub.6 H.sub.3 and C.sub.     H.sub.2 denote unsubstituted, monosubstituted, disubstituted and     trisubstituted phenyl groups, respectively. The formulae of these     substituents are shown, preceded by their positional number(s).     "Salt" column:     08 denotes the fumarate     1/2 08 denotes the hemifumarate     10 denotes the hydrochloride     2.10 denotes the dihydrochloride     15 denotes the methanesulphonate     46 denotes the oxalate     2.46 denotes the dioxalate

The compounds of the invention were subjected to various pharmacologicaltests to demonstrate their therapeutic activity.

Thus, for example, their antagonistic action towards the effects ofcalcium was studied on isolated rabbit aorta.

The experimental protocol used is a variant of that of Godfraind andKaba [Blockade or reversal of the contraction induced by calcium andadrenaline in depolarized arterial smooth muscle, Br. J. Pharmac.,(1969), 36, 549-560]. The experiments were carried out on sections ofrabbit thoracic aorta. The animals, "Fauves de Bourgogne" weighing onaverage 1.5 kg, were sacrificed by cervical dislocation andexsanguination. The thoracic aorta was rapidly removed and placed in anoxygenated Krebs bicarbonate medium (95% O₂ +5% CO₂).

Sections of aorta approximately 1 cm long were prepared and installed in20-ml organ cells containing oxygenated Krebs bicarbonate solution at pH7.4 at 37° C. Two U-shaped metal hooks having the same length as thesections were introduced into the bore of aorta sections. One of thehooks was attached to the base of the cell and the other, connected toan isometric strain gauge (Grass FTO3), permitted the recording, via acontinuous preamplifier (Grass 7P1), of the contractile responses of thesections of aorta on a pen oscillograph (Grass 79B). Compared withspiral or ring-shaped preparations, this method has the advantage ofhaving greater regard for the structural integrity of the vessels, andof recording only the radical component of the contractile responses,which represents the phenomenon of interest from the functionalstandpoint (regulation of arterial blood pressure). An initial tensionof 4 g was applied to the preparations.

Phenoxybenzamine (1 μM) and propranolol (1 μM) were added to thedifferent Krebs media to abolish the contractile responses linked to theactivation of the vascular α- and β-adrenergic receptors.

After one hour's stabilization in the Krebs medium, the tension appliedto the aorta sections was reduced to 2 g, and then, after a delay of 30minutes, the preparations were incubated for about 10 minutes in a Krebsbicarbonate solution without calcium in the presence of EDTA (200 μM)and propranolol (1 μM). This solution was then replaced by adepolarizing Krebs medium (rich in potassium) without calcium andcontaining propranolol (1 μM). After 5 minutes, a single concentrationof 1 mM of calcium was added to this solution and a stabilization periodof 30 minutes was observed, which enables the preparations to achievestable contraction.

Cumulative doses of the test compounds were then administered every 30minutes (the time generally necessary for obtaining a plateau), untilthere was complete disappearance of the contraction induced by 1 mMcalcium, or alternatively, until a 30 μM concentration of the testproduct was obtained.

At the end of the experiment, a supramaximal concentration of papaverine(300 μM) was administered to determine the maximum possible relaxationof each preparation.

The absolute values (in grams) of the initial contraction (after 1 mMcalcium chloride) and of the contraction after the different cumulativeconcentrations of vasodilatory compounds were obtained, for eachpreparation, by their differences with the minimal contraction observed30 minutes after the final addition of 300 μM papaverine. The percentagedecrease in the contraction, relative to the contraction induced by 1 mMcalcium, was calculated for each dose of compound and each preparation,and the mean X±SEM of the individual percentages was calculated. Themeans obtained (weighted by the reciprocal of the standard error of themean) were analyzed using a mathematical sigmoid curve model, and themolar concentration inducing 50% relaxation of the response to calcium(EC₅₀) was calculated.

For the compounds of the invention the EC₅₀ values generally are from0.2 to 10 μM.

The compounds of the invention were also subjected to a test of binding[³ H]nitrendipine to whole rat cortex.

Sprague-Dawley male rats weighing 150 to 200 g were used. After cervicaldislocation, the brain was excized and the cerebral cortex dissected ona culture dish in ice. It was placed in 20 volumes of an ice-cold 50 mMtris(hydroxymethyl)aminomethane buffer solution whose pH had beenadjusted to 7.4 with hydrochloric acid ("Tris-HCl" buffer). The tissuewas homogenized using a Polytron Ultra-Turrax apparatus for 30 secondsat one half maximum speed, and the preparations were washed three timeswith the ice-cold buffer solution, draining them each time bycentrifugation at 49,000×g for 10 minutes. Finally, suspensions wereprepared containing 100 mg of tissue in 1 ml of 30 mM Tris-HCl buffer(pH 7.4 at 37° C.)

100-μl aliquot portions of the suspension of washed membranes were thenincubated with [³ H]nitrendipine (New England Nuclear, specific activity70.0 Ci/mmol) in a final volume of 1 ml of Tris-HCl buffer. After 30minutes' incubation at 37° C., the membranes were recovered byfiltration on Whatman GF/F glass fibres, and washed three times with 5ml of ice-cold Tris-HCl buffer. The quantity of radioactivity bound tothe tissue and retained on the filters was measured by scintillationspectrometry. The specific binding of [³ H]nitrendipine is defined asthe decrease in the quantity of radioligand retained on the filter dueto the introduction of 1 μM nifedipine during the incubation. Thespecific binding represents 80 to 90% of the total quantity ofradioactivity collected on the filter. Using different concentrations oftest compounds, the IC₅₀ concentration, the concentration of the testcompounds which inhibits 50% of the specific binding of [³H]nitrendipine was determined graphically.

The IC₅₀ concentrations of the compounds of the invention generally arefrom 0.005 to 0.1 μM.

Finally, the compounds of the invention were studied in respect of theirantihypertensive effect in spontaneously hypertensive rats.

The systolic pressure was measured by means of a catheter placed in thecaudal artery, according to the method of Gerold and Tschirky(Arzneim.-Forsch., 1968 18, 1285-1287), and the pressure changes wererecorded in terms of the time elapsed, for each test compound and foreach dose administered. The compounds of the invention produce adecrease in the blood pressure of 15 to 30% after 30 minutes, and of 20to 25% after 3 hours, at doses of 5 to 30 mg/kg administeredintraperitoneally.

The results of the pharmacological tests show that the compounds of theinvention are calcium antagonists, and they can, on this ground, be usedfor the treatment of various conditions for which this type of agent isindicated.

Thus, in particular, they may be used in cardiovascular medicine for thetreatment of conditions requiring modulators of the transmembraneous andintracellular movements of calcium, most especially hypertension, anginaand cardiac arrhythmia.

They may, in addition, possess anti-atherogenic, platelet-aggregationinhibitory, cardiac-anti-ischaemic, cerebral anti-ischaemic,antimigraine, antiepileptic, antiasthmatic and antiulcer effects. In thecardiovascular field, they may be used alone or in combination withother known active substances such as diuretics, β-blockers,angiotensin-converting enzyme inhibitors and α₁ -receptor antagonists.

In combination with agents designed to boost their effects or decreasetheir toxicity, they may also be indicated for the treatment of canceror in transplantation.

The compounds of the invention may be presented in any form suitable fororal or parenteral administration, in combination with known excipients,for example in the form of tablets, gelatin capsules, dragees, capsules,and solutions or suspensions to be taken by mouth or injected.

The daily dosage can range, for example, from 5 to 200 mg orally andfrom 0.1 to 10 mg parenterally.

We claim:
 1. A compound of formula (I) ##STR42## wherein: X is selectedfrom the group of substituents consisting of a hydrogen, a halogen, atrifluoromethyl group, a C₁ -C₄ alkyl group and a C₁ -C₄ alkoxy group;R₁is selected from the group of substituents consisting of a liner orbranched C₂ -C₈ alkyl group, a C₃ -C₅ cycloalkyl group and acycloalkylmethyl group in which the cycloalkyl moiety has from 3 to 5carbon atoms; R₂ is hydrogen or a C₁ -C₄ alkyl group; R₃ is selectedfrom the group consisting of hydrogen, a C₁ -C₄ alkyl group, anunsubstituted phenylalkyl group, and a phenylalkyl group substitutedwith at least one substituent; wherein said substituent on saidphenylalkyl group is selected from the group consisting of a methoxygroup, a methylenedioxy group, a nitro group, a fluoro, a chloro and anacetylamino group; and Ar is a phenyl group that is unsubstituted or issubstituted with from one to three substituents, each of which is,independently, a halogen or a C₁ -C₄ alkyl, C₁ -C₄ alkoxy,trifluoromethyl, nitro or cyano group or Ar is a naphthyl group;or apharmacologically acceptable acid addition salt thereof.
 2. A compoundaccording to claim 1 wherein R₁ denotes an isobutyl group and Ar denotesa substituted phenyl group.
 3. A compound according to claim 2 wherein Xdenotes hydrogen and R₂ denotes a methyl group.
 4. A compound accordingto claim 3 wherein R₃ denotes a methyl group and Ar denotes a2,3-dimethylphenyl group.
 5. A compound according to claim 3 wherein R₃denotes a methyl group and Ar denotes a 3-trifluoromethylphenyl group.6. A compound according to claim 3 wherein R₃ denotes a methyl group andAr denotes a 3-nitrophenyl group.
 7. A compound according to claim 3wherein R₃ denotes a methyl group and Ar denotes a2-methoxy-5-nitrophenyl group.
 8. N-[4-{[2-(3-methoxyphenyl)ethyl]methyl amino}butyl]-N-[2-(2-methylpropoxy)phenyl]-3-(trifluoromethyl) benzamide. 9.N-[4-{[2-(3,4-dimethoxy phenyl)ethyl]methylamino}-butyl]-N-[2-(2-methyl-propoxy)phenyl]-3-(trifluoromethyl)benzamide.
 10. A compound according to claim 3 wherein Ar denotes a3-trifluoromethylphenyl group.
 11. N-[4-2-(3,4-dimethoxyphenyl)ethyl]methylaminobutyl]-N-[2-(2-methyl-propoxy)phenyl]-2-methyl-3-nitro benzamide.
 12. Apharmaceutical composition comprising a compound of formula (I) asdefined in claim 1 and a pharmaceutical excipient.
 13. A method oftreatment of hypertension, angina, atherosclerosis,platelet-aggregation, cardia arrhythmia, cardiac ischamia, cerebralischaemia, migraines, epilepsy, asthma, ulcer or which comprisesadministering to a subject in need of such treatment an effective amountof a compound as defined in claim
 1. 14. A compound according to claim 1wherein R₃ is a phenylalkyl group substituted by methoxy.
 15. A compoundaccording to claim 1 wherein R₃ is a phenylalkyl group substituted byNO₂.
 16. A compound according to claim 1 wherein R₃ is a phenylalkylgroup substituted by Cl or F.
 17. A compound according to claim 1wherein R₃ is a phenylalkyl group substituted by NHCOCH₃.